Uridine-5-monophosphate compositions

ABSTRACT

Pharmaceutical compositions characterized by accelerating action for glucuronide formation comprising uridine-5&#39;&#39;-monophosphate or its pharmaceutically acceptable salt in admixture with pharmaceutical carriers.

United States Patent Tamura [111 3,852,433 [4 Dec. 3, 1974URIDINE-S-MONOPHOSPHATE COMPOSITIONS Shunkichi Tamura, Funabashi, JapanInventor:

Assignee: Yamasa Shoyu Kabushiki Kaisha,

Chiba-ken, Japan Filed: Apr. 6, 1973 Appl. No.: 348,658

U.S. Cl .i 424/180, 260/112.5, 260/211.5 R,

260/343.7, 260/251 Int. Cl. AUln 9/00, AOln 9/28 Field of Search424/180; 260/211.5 R

References Cited] OTHER PUBLICATIONS Chem. Abstracts, (1964), Vol. 68,paragraph 16, 649(h).

Primary ExaminerElbert L. Roberts Attorney, Agent, or Firm-Wender0th,Lind & Ponack [5 7] ABSTRACT Pharmaceutical compositions characterizedby accel 8 Claims, N0 Drawings The present invention relates topharmaceutical compositions comprising uridine-S -monophosphate or itspharmaceutically acceptable salt having accelerating action forglucuronide formation and to methods using the same.

Glucruronide formation is a most typical one of detoxication mechanismsin a living body and uridinemonophosphate is known to be a biochemicalprecursor of uridine-S'-diphosphate-glucuronic acid which functions as aglucuronyl donor in the glucuronide formation. However, its use as apharmaceutical agent has not been investigated.

According to the present invention, it has been found thaturidine-5'-monophosphate is a potent accelerator for the glucuronideformation.

Hitherto, sulfur-containing amino acids and peptides, such asmethionine, cysteine, and glutathione, have been used clinically asbiochemical antidotes. These compounds are known to participate indetoxication by accelerating oxidation-reduction reaction and amine acidconjugation in vivo. However, these reactions are not primary indetoxication.

On the other hand, according to the present invention,uridine-S'-m0.nophosphate has been found to be a potent accelerator forthe glucuronide conjugation which is a most important reaction indetoxication in living bodies. Accordingly, uridine-5'-monophosphatecan-be considered to be a novel biochemical antidote different from theknown biochemical antidotes such as methionine, cysteine and glutathionein point of the drug action.

Thus, the administration of uridine-5- monophosphate is to be aneffective method of treating not only detoxication disturbances, inwhich his desired to obtain an increase in the glucuronide formingability such as liver-failure, but also various metabolic diseases-whichare caused by a decrease in the glucuronide forming ability such asicterus-neonatorium, Gilberts disease.

It is therefore the primary object of the present inventionto provide apharmaceutical composition having accelerating action for glucuronideformation which contains, as an active ingredient, uridine-5-monophosphate-glucuronic acid or its pharmaceutically acceptable salts,in admixture with a pharmaceutical carrier.

According to the present invention, there is provided a pharmaceuticalcomposition as an accelerator for glucuronide formation in dosage unitform comprising uridine-5'-monophosphate or its pharmaceuticallyacceptable salt as active ingredient and a pharmaceutical carrier.

The foregoing object as well as efflcaciousness of the present inventionwill become more apparent from the following detailed descriptionthereof.

The carrier can be either solid pharmaceutical carrier or diluent whenintended for oral administration or as a suppository, or sterileinjectable liquid pharmaceutical carrier or diluent when intended forparenteral administration,,or liquid pharmaceutical carrier or diluentpossibly in admixture with sweetening and/or flavoring agent whenintended for oral administration.

The pharmaceutical composition according to the present invention can beutilized in any of the dosage forms conventionally used for oral orparenteral administration. i

As the dosage form suitable for oral administration, powder, tablets,pills, capsules and dragees may be mentioned as examples.-

The composition may be associated with the conventional carrier ordiluent such as lactose, starch, calcium phosphate, talc, magnesiumstearate, polyvinyl pyrrolidone, carboxymethyl cellulose and gelatine.

The liquid composition for oral administration may preferably be used inthe form of syrup, emulsion or suspension, in which a sweetening agentsuch as sucrose, fructose, glucose, mannitol, sorbitol, and/or flavoringagents such as cherry, fruit, orange, mint, may be added.

The suppository is suitable for rectal administration. As a substrate,cacao butter, for example, may be used.

When the composition is to be used for parenteral administration, theymust be sterile, and used in the form of ampoules or vials with sterileinjectable liquid pharmaceutical carrier or diluent such as sterileinjectable water and physiological saline.

The present composition may be used in association with the knownbiochemical antidotes such as methionine, cysteine and glutathione, aswell as with vitamins such as vitamin B group and vitamin C.

In case of treating human beings, the average daily dose is in generalbetween 20 and 1,000 mg or more preferably between 50 and 500 mg.

The results of toxicological and pharmacological tests on sodium salt ofuridine-5-monophosphate (so dium salt of UMP) are as follows.

(I) ACUTE TOXICITY Table I Average Lethal Dose Route of (LD 50) mglkgAdministration Mouse Rat P.O. 12,000 l2,000 S.C. 4,416 6,000 LP. 3,5223J6) Note:

R0. oral, administration SC. subcutaneous administration LP.intraperitoncal administration (ll) EFFECTS ON GEUCURONIDE FORMATION INLIVER Wistar-albino rats, each having an average weight of g, were usedas test animals. Glucuronide formation in liver was determined by usingO-aminophenol as substrate.

(Experiment 1) 10 mg/kg of sodium salt of UMP, dissolved in 0.5 ml ofphysiological saline, were then intraperitoneally administered to therats once in a day. After 3 days, rats were killed by decapitation.O-amimophenyl glucuron- 3 4 ide formation was determined by using liverslice prepg g P 50 aration.

This experiment was carried out after the administra- -Continued tion ofphysiological saline had been proved to have no Limo 30 effect on theglucuronide formation in liver. 5

The results are shown in Table II below assuming that glucuronideformation in physiological salineadministered rats is 100.

The above components were uniformly mixed and prepared as powder.

T bl [I EXAMPLE 5 (CAPSULES) Glucuronide Compound Formation Sodium saltof UMP 100 mg Methionine 100 do.

NaCl 1000 Thiamine hydrochloride do.

Sodium salt 152.1 Calcium P p 100 do.

of UMP dibasic Talc 10 do.

The above ingredients were uniformly mixed and filled into a capsule.

EXAMPLE 6 (TABLETS) (Experiment 2) The relationship between the dosageof UMP-Na and the accelerating action forO-aminophenyl glucuronideformation was investigated.

The experimental method was the same as that in Ex- Sodium Salt of UMP100 mg periment l. The results are shown in Table III below. Thiaminehydrochloride 2 do. Ascorbic acid l0 do. Lactose 155 do. Table I Starchdo. Magnesium stearate 3 do.

Dosage Glucuronide (mg/kg) Formati n The above components were mixeduniformly and 30 made up into a tablet having a diameter of 10.0 mm.Control (NaCl) I00 x 1435 What I claim is: i3 5; l. A pharmaceuticalcomposition as an accelerator l 5 54:9 for glucuronide formation indosage unit form comprising an effective amount of uridine-S'monophosphate or its pharmaceutically acceptable salt as active ingre-AS is clear from Tables I, I, and sodium salt Of dient and apharmaceutical arfi'er "l P fixhibits y toxicity 2. The pharmaceuticalcomposition according to a P acceleratmg actlon for glucuromde forma'claim 1, wherein each dosage unit contains from 50 mg hverto 500 mg ofuridine-5-monophosphate as its sodium The dosage forms of the presentinvention are shown 40 salt in the following examples" 3. Thepharmaceutical composition according to EXAMPLE 1 (VIALS) claim 1,further containing a substance selected from the group consisting ofmethionine, cysteine and glutathione as a biochemical antidote.

4. The pharmaceutical composition according to claim 1, furthercontaining a vitamin selected from the EXAMPLE 2 (AMPOULES) groupconsisting of group B vitamins and vitamin C.

200 mg of sodium salt of UMP, pyrogen-free, was dis- The pharmaceuiwalmp according to solved in 2 ml of distilled water for injection, filledinto clam further contammg a vltamm Selected from the 200 mg of sodiumsalt of UMP, pyrogen-free, was dissolved in 2 ml of distilled water forinjection into a vial, 45 and lyophilized in vaccuo.

an ampoule and sterilized. group consisting of group B vitamins andvitamin C.

1 6. A method of administering to humans, a pharma- EXAMPLE 3 (TABLETS)ceutical composition as an accelerator for glucuronide formation indosage unit form comprising an effective Sodium San of UMP 100 mg amountof uridine-5'- monophosphate or its pharma- Lactose 90 do. ceuticallyacceptable salt, as the accelerator for glucug g3: ronide formation, anda pharmaceutical carrier.

Magnesium ar 2 do. 7. A method according to claim 6 wherein each dosageunit contains 50 mg. to 500 mg. of uridine-5- The above components wereuniformly mixed, and monophosphate as its sodium salt. formed into 3Fable! having a diameter f 8. A method according to claim 7 wherein thephar- EXAMPLE 4 POWDER) maceutical composition further contains asubstance selected from the group consisting of methionine, cysteine andglutathione as a biological antidote. Sodium Sill! of UMP 20 g 1

1. A PHARMACEUTICAL COMPOSITION AS AN ACCELERATOR FOR GLUCURONIDEFORMATION IN DOSAGE UNIT FORM COMPRISING AN EFFECTIVE AMOUNT OFURIDINE-5''-MONOPHOSPHATE OR ITS PHARMACEUTICALLY ACCEPTABLE SALT ASACTIVE INGREDIENT AND A PHARMACEUTICAL CARRIER.
 2. The pharmaceuticalcomposition according to claim 1, wherein each dosage unit contains from50 mg to 500 mg of uridine-5''-monophosphate as its sodium salt.
 3. Thepharmaceutical composition according to claim 1, further containing asubstance selected from the group consisting of methionine, cysteine andglutathione as a biochemical antidote.
 4. The pharmaceutical compositionaccording to claim 1, further containing a vitamin selected from thegroup consisting of group B vitamins and vitamin C.
 5. Thepharmaceutical composition according to claim 3, further containing avitamin selected from the group consisting of group B vitamins andvitamin C.
 6. A method of administering to humans, a pharmaceuticalcomposition as an accelerator for glucuronide formation in dosage unitform comprising an effective amount of uridine-5''-monophosphate or itspharmaceutically acceptable salt, as the accelerator for glucuronideformation, and a pharmaceutical carrier.
 7. A method according to claim6 wherein each dosage unit contains 50 mg. to 500 mg. ofuridine-5''-monophosphate as its sodium salt.
 8. A method according toclaim 7 wherein the pharmaceutical composition further contains asubstance selected from the group consisting of methionine, cysteine andglutathione as a biological antidote.